Chronic itch is a presenting sign in numerous diseases associated with the skin, immune and nervous systems. Chronic itch is largely resistant to conventional antihistamines, and few effective therapies are available. In order to develop novel therapeutics against chronic itch, there is a pressing need for identification of itc-specific signaling mechanisms involved. Activation of kappa opioid receptor (KOR) can inhibit chronic itch. However, KOR activation is associated with several side effects that might have hindered its use as therapeutics. We recently found that gastrin-releasing peptide receptor (GRPR) is an important receptor for the development of chronic itch, and KOR activation attenuates itch by inhibiting GRPR function. Aim 1 is to determine whether KOR inhibits itch by a blockade of GRPR function. Aim 2 is to examine the role of PKC in KOR activation-mediated inhibition. Aim 3 is to determine whether KOR activation inhibits itch via KOR-GRPR heteromerization. The proposed studies are highly translational because it will provide mechanistic insights into KOR-mediated inhibition of chronic itch and will significantly expand the pool of the targets that may be explored for future KOR-GRPR-based anti-pruritus drug discovery program.